T Cell Receptor Immunotherapy Targeting HPV-16 E6 for HPV-Associated Cancers

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Brief Title

T Cell Receptor Immunotherapy Targeting HPV-16 E6 for HPV-Associated Cancers

Official Title

A Phase I/II Study of T Cell Receptor Gene Therapy Targeting HPV-16 E6 for HPV-Associated Cancers

Brief Summary


      The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for
      treating patients with cancer that involves taking white blood cells from the patient,
      growing them in the laboratory in large numbers, genetically modifying these specific cells
      with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells
      back to the patient. This type of therapy is called gene transfer. Researchers want to test
      this on human papilloma virus (HPV)-associated cancers.


      - The purpose of this study is to determine a safe number of these cells to infuse and to see
      if these particular tumor-fighting cells (Anti-HPV E6) can shrink tumors associated with HPV
      and test the toxicity of this treatment.


      - Adults age 18-66 with an HPV-16-associated cancer.


        -  Work up stage: Patients will be seen as an outpatient at the National Institutes of
           Health (NIH) clinical Center and undergo a history and physical examination, scans,
           x-rays, lab tests, and other tests as needed

        -  Leukapheresis: If the patients meet all of the requirements for the study they will
           undergo leukapheresis to obtain white blood cells to make the anti HPV E6 cells.
           {Leukapheresis is a common procedure, which removes only the white blood cells from the

        -  Treatment: Once their cells have grown, the patients will be admitted to the hospital
           for the conditioning chemotherapy, the anti HPV E6 cells and aldesleukin. They will stay
           in the hospital for about 4 weeks for the treatment.

      Follow up: Patients will return to the clinic for a physical exam, review of side effects,
      lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1
      year as long as their tumors are shrinking. Follow up visits take up to 2 days.

Detailed Description


        -  Metastatic or refractory/recurrent human papillomavirus (HPV)-16+ cancers (cervical,
           vulvar, vaginal, penile, anal, and oropharyngeal cancers) are incurable and poorly
           palliated by standard therapies.

        -  HPV-16+ cancers constitutively express the HPV-16 E6 oncoprotein, which is absent from
           healthy human tissues.

        -  Administration of T cell receptor (TCR) gene engineered T cells can induce objective
           tumor responses in certain malignancies.

        -  T cells genetically engineered with a TCR targeting HPV-16 E6 (E6 TCR) display specific
           reactivity against human leukocyte antigen serotype within HLA-A A serotype group
           (HLA-A2+), HPV-16+ target cells.


      Primary Objective

        -  To determine a safe dose of administration of autologous T cells transduced with an
           anti-HPV-16 E6 TCR and aldesleukin to patients following a nonmyeloablative but
           lymphodepleting preparative regimen.

        -  To determine the objective tumor response rate (Complete or Partial Response) and
           duration in patients with metastatic or recurrent/refractory HPV-16+ cancers treated
           with this regimen.


        -  Patients greater than or equal to 18 years old and less than or equal to 70 years old
           with metastatic or refractory/recurrent HPV-16+ cancer.

        -  Prior first line systemic therapy is required unless the patient declines standard

        -  Patients must be HLA-A 02:01-positive.


        -  Patients will receive a non-myeloablative lymphocyte-depleting preparative regimen of
           cyclophosphamide and fludarabine

        -  On day 0 patients will receive transduced lymphocytes and then begin high dose

        -  The study will begin with a phase I dose escalation. After the maximum tolerated dose
           (MTD) cell dose has been determined, the patients will be enrolled into the phase II
           portion of the study.

        -  Clinical and immunologic response will be evaluated about 4 to 6 weeks after treatment
           and then about every 1-6 months until disease progression

        -  Following a dose escalation phase of 9 to 18 patients, initially 21 evaluable patients
           will be enrolled in the phase II portion of the study. If 0 to 1 of the 21 patients
           experiences a clinical response, then no further patients will be enrolled. If 2 or more
           of the first 21 evaluable patients enrolled have a clinical response, then accrual will
           continue until a total of 41 evaluable patients have been enrolled. The accrual ceiling
           will be set at 61 patients. Provided that about 1 patient every 6 weeks will be enrolled
           onto this trial, approximately 4 years may be needed to accrue the maximum number of

Study Phase

Phase 1/Phase 2

Study Type


Primary Outcome

Maximum Tolerated Dose (MTD)

Secondary Outcome

 Number of Participants With Serious and Non-serious Adverse Events


Vaginal Cancer



Study Arms / Comparison Groups

 T Cell Receptor Immunotherapy
Description:  patients will receive cyclophosphamide and fludarabine followed by infusion of the human papilloma virus (HPV) E6 T cell receptor (TCR), followed by high dose aldesleukin


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

October 14, 2014

Completion Date

June 28, 2016

Primary Completion Date

June 28, 2016

Eligibility Criteria


          1. Measurable metastatic or refractory/recurrent human papilloma virus (HPV-16+) cancer
             (determined by in situ hybridization (ISH) or a polymerase chain reaction (PCR)-based

          2. Patients must be human leukocyte antigens (HLA-A) 02:01-positive.

          3. All patients must have received prior first line standard therapy or declined standard
             therapy, and have been either non-responders (progressive disease) or have recurred.

          4. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and
             asymptomatic are eligible. Lesions that have been treated with stereotactic
             radiosurgery must be clinically stable for 1 month after treatment for the patient to
             be eligible. Patients with surgically resected brain metastases are eligible.

          5. Greater than or equal to 18 years of age and less than or equal to 70 years of age.

          6. Able to understand and sign the Informed Consent Document.

          7. Willing to sign durable power of attorney

          8. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.

          9. Life expectancy of greater than 3 months.

         10. Patients of both genders must be willing to practice birth control from the time of
             enrollment on this study up to 4 months after treatment. Patients must be willing to
             undergo testing for HPV-16 prior to becoming pregnant.

         11. Women of child bearing potential must have a negative pregnancy test because of the
             potentially dangerous effects of the treatment on the fetus.

         12. Serology:

               -  Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental
                  treatment being evaluated in this protocol depends on an intact immune system.
                  Patients who are HIV seropositive can have decreased immune-competence and thus
                  are less responsive to the experimental treatment and more susceptible to its

               -  Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody.
                  If hepatitis C antibody test is positive, then the patient must be tested for the
                  presence of antigen by reverse transcription polymerase chain reaction (RT-PCR)
                  and be hepatitis C virus ribonucleic acid (HCV RNA) negative.

         13. Hematology:

               -  Absolute neutrophil count greater than 1000/mm^3 without the support of

               -  White blood cell (WBC) greater than or equal to 3000/mm^3

               -  Platelet count greater than or equal 100,000/mm^3

               -  Hemoglobin greater than 8.0 g/dL

         14. Chemistry:

               -  Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than
                  or equal to 2.5 times the upper limit of normal

               -  Serum creatinine less than or equal to 1.6 mg/dL

               -  Total bilirubin less than or equal to to 1.5 mg/dL, except in patients with
                  Gilberts Syndrome who must have a total bilirubin less than 3.0 mg/dL

         15. More than 4 weeks must have elapsed since any prior systemic therapy at the time the
             patient receives the preparative regimen.


          1. Women of childbearing potential who are pregnant or breastfeeding. There are
             potentially dangerous side effects of the treatment on the fetus or infant.

          2. Active systemic infections (for e.g.: requiring anti-infective treatment), coagulation
             disorders or other active major medical illnesses of the cardiovascular, respiratory
             or immune system, as evidenced by a positive stress thallium or comparable test,
             myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary

          3. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency

          4. Concurrent opportunistic infections (The experimental treatment being evaluated in
             this protocol depends on an intact immune system. Patients who have decreased immune
             competence may be less responsive to the experimental treatment and more susceptible
             to its toxicities).

          5. Concurrent systemic steroid therapy.

          6. History of severe immediate hypersensitivity reaction to cyclophosphamide or

          7. History of coronary revascularization or ischemic symptoms.

          8. Documented left ventricular ejection fraction (LVEF) of less than or equal to 45%
             tested. The following patients will undergo cardiac evaluations

        a. clinically significant atrial and/or ventricular arrhythmias including but not limited
        to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or

        b. age greater than or equal 60 years old




18 Years - 70 Years

Accepts Healthy Volunteers



Christian S Hinrichs, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party

Principal Investigator

Study Sponsor

National Cancer Institute (NCI)

Study Sponsor

Christian S Hinrichs, M.D., Principal Investigator, National Cancer Institute (NCI)

Verification Date

August 2017